This invention relates to new pharmaceutical compositions and to pharmaceutical compositions having activity against diseases caused by or related to overproduction or localised high concentration of nitric oxide in the body.
Nitric oxide (NO) plays a varied and vital role in the human body. For example, NO plays a vital role in the control of blood pressure; it acts as a neurotrasmitter; it plays a role in inhibition of platelet aggregation (important in thrombosis or blockages of the blood vessels), and in cytostasis (important in fighting of tumours). Overproduction of NO however, has been implicated in a number of disease states, including vascular/pressor diseases such as septic shock, post-ischaemic cerebral damage, migraine, and dialysis induced renal hypotension; immunopathologic diseases such as hepatic damage in inflammation and sepsis, allograft rejection, graft versus host diseases, diabetes and wound healing; neurodegenerative diseases such as cerebral ischaemia, trauma, chronic epilepsy, Alzheimer""s disease, Huntington""s disease, and AIDS dementia complex; and side effects of treatment such as restenosis following angioplastic treatment and secondary hypotension following cytokine therapy.
Pharmacological modulation of nitric oxide in any of these disease states should prove extremely beneficial.
One above-mentioned disease relating to overproduction of NO, is septic shock. This is precipitated by local septicaemia or endotoxaemia, (high local levels of bacterial endotoxins). The result is activation of macrophages, lymphocytes, endothelial cells and other cell types capable of producing NO, further mediated by cytokine production by these cells. The activated macrophages produce excess NO which causes vasodilation of the blood vessels, and results in local vascular damage and vascular collapse. This destruction of vascular integrity may be so great that it leads to the collapse of haemodynamic homeostasis, the end result being death.
Current ideas for pharmacological modulation of nitric oxide in such diseases are based on dealing with the mediators of septic shock, such as cytokines, endotoxins, and platelet activating factor (PAF). The approaches include use of antibodies to cytokines such as tumour necrosis factor (TNF), receptor antagonists such as interleukin 1, (IL-1), antibodies to lipopolysaccharide (the endotoxin produced by gram negative bacteria, and PAF antagonists. All such approaches while challenging a factor mediating septic shock, do not attempt to deal with the aetiology, or cause, of the disease. Recent advances in understanding of NO have lead to the proposal that inhibitors of the NO synthase enzyme, such as NG-monomethy-L-arginine (L-NMMA), may be useful in the treatment of septic shock and other NO overproduction related to diseases since they inhibit NO production. While these inhibitors have shown some utility in animal models and preliminary clinical studies, they have the disadvantage of undesirably inhibiting total NO synthesis in the body.
An aim of the present invention is to provide new and previously indicated pharmaceutical compositions which are able to modulate NO levels in the body by scavenging, or removing, NO in situ so that necessary NO synthesis continues while dangerous excesses are removed. We have found that certain metal complexes have the ability to carry out this important role.
Some metal complexes are known in pharmaceutical compositions for the treatment of diseases of the human body. For example, certain complexes of platinum and ruthenium have been used or indicated in the treatment of cancer. Metal complexes have not however been previously indicated in the treatment of NO overproduction related diseases.
This invention provides for the use of a neutral, anionic or cationic metal complex having at least one site for coordination with NO, of formula
[Ma(XbL)cYdZe]axc2x1xe2x80x83xe2x80x83formula I,
in the manufacture of a medicament for the attenuation of NO levels where NO is implicated in disease,
where: M is a metal ion or a mixture of metal ions;
X is a cation or a mixture of cations;
L is a ligand, or mixture of ligands each containing at least two different donor atoms selected from the elements of Group IV, Group V or Group VI of the Periodic Table;
Y is a ligand, or a mixture of the same or different ligands each containing at least one donor atom or more than one donor atom, which donor atom is selected from the elements of Group IV, Group V or Group VI of the Periodic Table; and
Z is a halide or pseudohalide ion or a mixture of halide ions and pseudohalide ions;
a=1-3; b=0-12; c=0-18; d=0-18; e=0-18; and n=0-10; provided that at least one of c, d and e is 1 or more;
and where c is 0; b is also 0;
and where a is 1; c, d and e are not greater than 9;
and where a is 2; c, d and e are not greater than 12.
By xe2x80x9ccomplexxe2x80x9d in this specification is meant a neutral complex or anionic or cationic species.
The term xe2x80x9cGroupxe2x80x9d which is used herein is to be understood as a vertical column of the periodic table in which elements of each Group have similar physical and chemical properties. The definition of the Periodic Table is that credited to Mendeleev; Chambers Dictionary of Science and Technology, 1974. Published by W and R Chambers Ltd.
This invention may also be stated as providing a method of attenuation of NO levels where NO is implicated in diseases of the human body, comprising administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of formula I.
This invention may also provide for the use of a neutral, anionic or cationic metal complex of formula I in the manufacture of a medicament for the treatment of NO overproduction related disease.
This invention may also be stated as providing a method of treatment of diseases of the human body resultant of overproduction of NO in the human body, comprising administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of formula I.
Where the formula I represents an anionic species, a cation will also be present. Where formula I represents a cationic species, an anion will also be present. The metal complexes may be hydrated.
Preferably, M is a first, second or third row transition metal ion. For example, M may be an Rh, Ru, Os, Mn, Co, Cr or Re ion, and is preferably an Rh, Ru or Os ion.
Suitably M is in an oxidation state III. We have found surprisingly that when the metal ion for example ruthenium is in oxidation state m, the rate at which it binds with NO is significantly faster than when it is in oxidation state IL
X may be any cation, such as a mono-, di- or tri-valent cation. Suitable cations may be H+, K+, Na+, NH4+ or Ca2+. Conveniently X may be H+, K+ or Na+.
Preferably, L is a ligand containing both nitrogen and oxygen donor atoms. Examples of suitable such ligands include ethylenediamine -N,Nxe2x80x2-diacetic acid (edda), ethylenedianinetetaacetic acid (edta), nitrilotriacetic acid (nta), dipicolinic acid (dipic), picolinic acid (pic), diethylenetriaminepentaacetic acid (dtpa), thiobis(ethylenenitrilo)tetraacetic acid (tedta), dithioethanebis(ethylene-nitrilo)tetraacetic acid (dtedta) and N-(2-hydroxyethyl)ethylenediamine-triacetic acid (hedtra).
Preferably, Y is a ligand containing nitrogen, oxygen, sulphur, carbon, or phosphorus donor groups. Suitable nitrogen donor groups may be for example ammine, amine, nitrile and nitride or derivations thereof. Suitable oxygen donor groups may be for example carboxylic acid, ester or derivations thereof, water, oxide, sulphoxide, hydroxide, acetate, lactate, propionate, oxalate and maltolate. Suitable sulphur donor groups may be for example sulphoxide, dialkylsulphide, dithiocarbamate or dithiophosphate. Suitable carbon donor groups may be for example carbon monoxide or isocyanide. Suitable phosphorus donor groups may be for example trialkylphosphine.
Z may be any halide and is preferably chloride, bromide or iodide. Most conveniently, Z is chloride.
Examples of metal complexes for use according to the present invention include optionally hydrated ruthenium complexes of formula
[Ru(H0-6Lxe2x80x3)1-3Y0-2Cl0-4](0-4)xc2x1xe2x80x83xe2x80x83formula II,
where Lxe2x80x3 is an amide or ester or derivative thereof, or a polydentate aminocarboxylate ligand, for example edta, nta, dipic, pic, edda, tropolone, dtpa, hedtra, tedta or dtedta or diamide of edta or dtpa or a mixture of any of these, and Y is as defined above and may for example be selected from acetylacetone (acac), a xcex2-diketonate, water, dimethylsulphoxide (dmso), carboxylate, bidentate carboxylate, catechol, kojic acid, maltol, hydroxide, tropolone, malonic acid, oxalic acid, 2,3-dihydroxynaphthalene, squaric acid, acetate, a sulphate and a glycolate. The skilled addressee will be able to substitute other known ligands at Y and which will fall within the scope of the inventions. Preparative methods of tedta, dtedta and diamide of edta and dtpa are described in the following references respectively:
P Tse and J E Powell, Inorg Chem, (1985), 24, 2727
G Schwartzenbach, H Senner, G Anderegg, Helv Chim Acta 1957, 40, 1886
M S Konings, W C Dow, D B Love, K N Raymond, S C Quay and S M Rocklage, Inorg Chem (1990), 29, 1488-1491
P N Turowski, S J Rodgers, R C Scarrow and K N Raymond, Inorg Chem (1988), 27, 474-481.
Where the complex of formula II is an anion, a cation will be required. For example the complexes of formula II are present in
K[Ru(Hedta)Cl]2H2O
[Ru(H2edta)(acac)]
K[Ru(hedtra)Cl]H2O
K[Ru(dipic)2]H2O
(H2pic)[RuCl2(pic)2](Hpic)H2O
K[Ru(H2edta)Cl2]H2O
K[Ru(Hnta)2]xc2xdH2O
K[Ru(H2dtpa)Cl]H2O
[Ru(Hhedtra)acac]H2O
[Ru(Hhedtra)trop]
[Ru(H3dtpa)Cl]
Complexes of formula II have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated ruthenium complex of formula II.
Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of formula III
[M1-3Y1-18Cl0-18](0-6)xc2x1xe2x80x83xe2x80x83formula III
Where Y is a sulphur donor ligand. For example, such complex is present in
[Ru(mtc)3] (mtc=4-morpholinecarbodithoic acid)
Ru(S2CNCH2CH2NMeCH2CH2)3xc2xdH2O
Complexes of formula III in which Y is a sulphur donor ligand have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of formula III wherein Y is a sulphur donor ligand.
Yet further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of formula
[Mxe2x80x2xe2x80x31-3Yxe2x80x2xe2x80x31-18Cl0-18](0-6)xc2x1xe2x80x83xe2x80x83formula III
where Mxe2x80x2xe2x80x3 is ruthenium and Yxe2x80x2xe2x80x3 is an oxygen-donor ligand such as acetate, lactate, water, oxide, propionate (COEt), oxalate (ox), or maltolate (maltol) or a combination of these. For example complexes of formula III are present in
[Ru3O(OAc)6](OAc)
[Ru3O(lac)6](lac)
[Ru2(OAc)4]NO3 
[Ru2(OCOEt)4]NO3 
K3[Ru(ox)3]
[Ru2(OAc)4]Cl
[Ru(maltol)3]
Some complexes of formula III have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of ruthenium of formula III wherein Mxe2x80x2xe2x80x3 is ruthenium and Yxe2x80x2xe2x80x3 is an oxygen-donor ligand selected from the group acetate, lactate, oxide, propionate and maltolate.
Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of formula
[RuYIV1-9Cl1-9](0-4)xc2x1xe2x80x83xe2x80x83formula IV
where YIV is a nitrogen-donor ligand such as ammine, ethylenediamine (en), pyridine (py), 1,10phenanthroline (phen), 2,2xe2x80x2-bipyridine (bipy) or 1,4,8,11-tetraazacyclotetradecane (cyclam), 2,3,7,8,12,13,17,18-octaethylporphyrin (oep) or a combination of these. For example complexes of formula IV are present in
[Ru(NH3)5Cl]C2 
[Ru(en)3]I3 
trans-[RuCl2(py)4]
K[Ru(phen)Cl4]
[Ru(cyclam)Cl2]Cl
K[Ru(bipy)Cl4]
[Ru(NH3)6]Cl3 
[Ru(NH3)4Cl2]Cl
Ru(oep)Ph
Some complexes of formula IV have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of ruthenium of formula IV wherein YIV is a nitrogen-donor ligand selected from the group en, py, phen, bipy, cyclam and oep. Derivations of these ligands can be prepared by a skilled addressee and which will fall within the scope of the inventions.
Still further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium or osmium of general formula
[M1-3YV1-18Cl0-18](0-6)xc2x1xe2x80x83xe2x80x83formula V
where YV is a combination of donor ligands such as are described hereinabove, for example amnmine, dmso, oxalate, bipy, acac and MeCN. Complexes of formula V are present in for example
[Ru(NH3)(dmso)2Cl3]
cis-[Ru(dmso)4Cl2]
cis-[Ru(NH3)(dmso)3Cl2]
[Ru(dmso)3Cl3]
[Os(ox)(bipy)2]H2O
[Ru(acac)2(MeCN)2]CF3SO3 
The complex ions of the latter two compounds above have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of formula [Os(ox)(bipy)2]; and further a pharmaceutical composition containing an optionally hydrated complex of formula [Ru(acac)2(MeCN)2]+.
In use the complexes of the present invention may be included as an active component in a pharmaceutical composition containing an optionally hydrated complex of any of formulae I-V, in admixture with a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition may be formulated according to well known principles, and may be in the form of a solution or suspension for parenteral administration in single or repeat doses or be in capsule, tablet, dragee, or other solid composition or as a solution or suspension for oral administration, or formulated into pessaries or suppositories, or sustained release forms of any of the above. The solution or suspension may be administered by a single or repeat bolus injection or continuous infusion, or any other desired schedule. Suitable diluents, carriers, excipients and other components are known. Said pharmaceutical composition may contain dosages determined in accordance with conventional pharmacological methods, suitable to provide active complexes in the dosage range in humans of 1 mg to 10 g per day. Actual required dosage is largely dependent on where in the body there is the excess concentration of NO and for how long overproduction continues or attenuation of NO levels, where NO is implicated in disease, is required.